Neurodegeneration in the retina of motoneuron diseases: a longitudinal study in amyotrophic lateral sclerosis and Kennedy’s disease

Amyotrophic lateral sclerosis (ALS), the most common form of motor neuron disease (MND), and Kennedy’s disease (KD), an inherited MND that affects males, are two paradigmatic neurodegenerative diseases that strongly differ in clinical course. ALS is characterized by rapid neurodegeneration of upper and lower motor neurons, leading to death within 2–5 years following the diagnosis [1]. KD, caused by a genetic mutation of the androgen receptor gene on the X chromosome, is characterized by a slowly progressive loss of lower motor neurons (determining atrophy of limb and facial muscles), associated with other symptoms, such as sensory deficits, gynecomastia, and infertility [2].

Asymptomatic retinal nerve fiber layer (RNFL) thinning was reported to occur in ALS and was associated with disease progression, suggesting that other brain functional systems might be affected by the disease [3‐5]. This observation, which constitutes a clinical/laboratory mismatch merits to be investigated given its pathogenic relevance. Moreover, no data are currently available on retina changes in other MND, particularly in KD.

Optical coherence tomography (OCT), a non-invasive imaging methodology that allows high-resolution analysis of retinal architecture and the measurement of its layers, is widely used to disclose early signs of neurodegeneration in brain inflammatory and neurodegenerative disorders. Indeed, thinning of the RNFL, the ganglion cell-inner plexiform layer (GCIPL), and the inner nuclear layer (INL) had been described in multiple sclerosis and dementia [6‐14]. However, to what extent atrophy of retinal layers in brain disorders is secondary to the neurodegenerative processes occurring in the brain (i.e., trans-synaptic degeneration) or is primarily a local independent phenomenon remains to be clarified. Moreover, the clinical value of retinal atrophy remains obscure.

To add light on retinal pathology and its possible use for clinical purposes in MND, we designed a longitudinal OCT study aimed at analyzing and comparing retinal layer changes in two paradigmatic motoneuron diseases, ALS and KD, characterized by different pathogenetic mechanisms, severity and duration.

Preliminary observations in ALS suggest that neurodegeneration is not confined to motor neurons but probably is a widespread pathological process that involves other functional systems of the central nervous system (CNS), such as the visual pathway [22]. Post-mortem studies disclosed neurodegeneration signs in the inner retinal layers of ALS patients, such as inclusion bodies and atrophy [23]. In vivo studies by OCT, although suggesting the involvement of retina, gave discordant results. While the majority of the studies agree on the significant thinning of RNFL compared to HC [3, 4, 22, 24], more contradictory data are available on INL atrophy [3, 22, 24‐26]. Moreover, while some studies found an association between RNFL thinning and both motor function decline [4, 27] and disease duration [28], others failed [5, 26, 29]. Our study adds light on the structural retinal changes and their clinical correlates in ALS, also by comparison with the retinal changes observed in KD, up to date unexplored. Indeed, we observed that RNFL was atrophic in both ALS and KD, but with differences in thinning rate and involved sectors. Namely, ALS was associated with a more diffuse and faster pRNFL temporal atrophy compared to KD which was instead characterized by a limited pRNFL involvement, namely in the TI and NI sectors (even if the latter was characterized by a high variance which did not allow to reach the significance), whose thickness did not change during the follow-up. Although the evolution of retinal thinning in ALS seems to evolve in parallel with motoneuron degeneration, according to other studies [5, 26, 29], RNFL atrophy did not show a correlation with disease duration and severity. This observation, in line with pathological observations [23] seems to support the hypothesis of a primarily local neurodegenerative process occurring in the retina, that encourages further investigations.

To our knowledge, this is the first report describing retinal atrophy in KD patients. Besides lower motoneuron degeneration, KD is characterized by a complex clinical picture that may include sensory neuropathy, gynecomastia, autonomic and sexual dysfunctions. For the first time, we described a selective thinning of the TI sector of pRNFL in KD, and its association with disease severity and duration. These findings are particularly interesting since CNS seems to be spared in KD [30]. However, in a few studies on a very small number of patients subtle pathological changes in the grey matter or white matter atrophy were described by means of non-conventional MRI sequences (for a review see [31]). Most of the changes, however, were observed in the motor system, predominantly affecting the cortical-spinal tract [32] or the frontal lobe and cerebellum [33], although changes in the limbic lobe were also found. Although, MRI was not routinely performed on our patients (the exam was not included in the diagnostic workup), no patient in our cohort had clinical signs and symptoms of brain pathology. Thus, a primary slowly progressive neuronal degeneration (i.e., not detectable in a one-year follow-up), seems to occur in the retina of KD.

As above mentioned, to what extent RNFL atrophy is a primary local neurodegenerative phenomenon or rather the effect of trans-synaptic degeneration due to pathological changes in the visual pathway is a matter of debate. Indeed, the significant decrease in RNFL thickness observed in ALS in one-year follow-up, apparently not correlated with the clinical picture, seems to indicate that a local neurodegenerative process occurs in the retina of ALS patients, thus supporting the view that motor neurons are not the only neuronal populations affected in this disease. Moreover, our data in KD, a disease apparently not involving the CNS, further support the view that retina may be the site of primary neurodegenerative phenomena, that merit to be deeply investigated. Indeed, the retina is an extension of the CNS, and measurements of retina layers, especially RNFL thickness by means of OCT may provide important information on the neurodegenerative processes taking place in the brain. To what extent retinal thinning might reflect the aggressiveness and rapidity of the disease progression in ALS need to be explored in larger patient cohorts. However, by comparison, the absence of detectable retinal thinning in KD in our follow-up window indicates that retinal changes in KD proceed more slowly.

We are aware that the missing longitudinal trajectory of retinal changes in the HC group, accounting for natural aging-related thinning, may constitute a limitation of our study. However, we would like to stress the explorative nature of our study which was aimed at pointing out retinal differences between the two most important MND and their clinical correlates. Moreover, although quite heterogenous, the clinical phenotype of our ALS population was consistent with the epidemiological prevalence of spinal-onset ALS, compared to bulbar-onset, obtaining a representative sample of the sporadic ALS. To what extent the site of onset and the degree of behavioral impairment may influence the correlation with retinal findings is still unknown and deserves further investigation in larger patient cohorts.

In conclusion, our study in subjects with ALS or KD has added some new information about retinal neurodegeneration in MND. Taken together, our findings seem to suggest that retinal atrophy is a phenomenon at least partly disconnected from the degenerative process that characterizes MND.